clinical oncology Flashcards
breast cancer: summarise the epidemiology of breast cancer, recall the pathological and clinical features of breast cancer, explain the pathophysiology of breast cancer, summarise the basis and role for endocrine therapies in treating breast cancer
investigations for breast cancer
consultation, clinical examintation, mammography, core needle biopsy
proportion of cancer deaths breast cancer is responsible for, and prevalence in UK
1/5 (leading female cancer), with 1/8 women in UK developing it
why is the incidence of breast cancer rising
early diagnosis by self-detection (promoted by NHS)
why is the mortality of breast cancer falling
early diagnosis, chemo/radiotherapies, hormonal (endocrine) therapies
describe the breast and what causes its formation and when
very fatty organ formed during puberty due to high levels of oestrogen, as well as progesterone, from ovary; collection of ducts and glands that meet at nippe
what type of cancer are most malignant breast cancers
in clinic, breast cancer is carcinoma (tumour of luminal epithelial cells); can rarely be sarcoma (but not “clinic breast cancer”)
cellular organisation of mammary gland
luminal (inner epithelial) cells in centre, with a layer of myoepithelial cells (outer epithelial cells forming tubules; some slightly vacuolated) surround them, making contact with basement membrane; during lactation, myoepithelial cells contract to squeeze milk through lumen
progression of normal to malignant breast: normal
myoepithelial cells, attached to basement membrane, surrounding luminal epithelial cells
progression of normal to malignant breast: benign/in situ carcinoma
proliferation of luminal epithelial cells into luminal cells, forming benign carcinoma, with myoepithelial cells becoming residual
progression of normal to malignant breast: 3 outcomes following benign/in situ carcinoma
medullary carcinoma (packed full of vesicles which don’t retain morphology of tubular-like structure), unspecified infiltrating ductal carcinoma, lobular carcinoma (tumour cells retain some morphology of tubular-like structure despite loss of myoepithelial cells)
what carcinoma accounts for almost 80% of breast cancersm and has no special type of histological structure
infiltrating ductal carcinoma
what does immunohistochemical staining use antibodies against in invasive breast cancer
human oestrogen receptor (ER)
% of infiltrating ductal carcinomas that are ER positive
80% (hence ER becomes test for cancer)
oestrogen-related risk factors for breast cancer
lifetime exposure of oestrogen, age of onset of menarche, age to first full-time pregnancy, some contraceptive pills, some HRT
oestrogen receptor (ER) pathway causing cancer
oestogen passes through membrane (steroid) and binds to oestrogen receptor (associated with hsp90) in cytoplasm -> sheds hsp90 protein and binds to another oestrogen receptor -> enters nucleus -> gene expression induced by receptor dimer/oestrogen complex binding to specific DNA sequences (oestrogen response elements; within minutes of oestrogen binding) -> oestrogen-induced gene products increase cell proliferation, resulting in breast cancer
4 important oestrogen regulated genes and function
progesterone receptor (PR; sensitising cells to respond to progesterone), cyclin D1 (regulation of cell cycle), c-myc (ensure survival and not apoptosis), TGF-a (direct growth factor)
normal vs tumour cells responding to oestrogen
in normal cells, oestrogen binds to ER and causes proliferation of surrounding cells; in tumour, oestrogen drives growth of tumour cells as well
fraction of premenopausal women with advanced breast cancer will respond to oophorectomy (removal of ovary)
1/3
describe paradoxical nature of breast cancer in postmenopausal women, and how this happens; describe consequence
respond to high-dose synthetic oestrogen to cause breast tumour regression (hormonal pathways set up so if over-stimulated, receptor becomes down-regulated so lose ability to respond); would relapse with metastatic disease
% of breast cancers where ER is overexpressed and respond to anti-oestrogens
70%; some ER negative also show some response to anti-oestrogens, but not all
what does an increased level of ER expression indicate in women vs men
in women, better prognosis as treatment, but in men (rare) a worse prognosis as less effective treatment (partially driven by androgen receptor)
4 major treatment approaches for breast cancer
surgery, radiotherapy, chemotherapy, endocrine therapy
what is the primary therapy for breast cancer usually
mastectomy (removal of breast) or lumpectomy (removal of tumour and small amount of normal tissue around it)
what is removed in breast surgery and why
(sentinel) lymph nodes to see if cancer cells have spread to lymphatics
what is conducted following a lumpectomy (breast-conserving surgery)
radiotherapy
endocrine therapy: define adjuvant therapy
treatment given after primary therapy to increase the chance of long-term disease-free survival by treating any metastasis broken off from tumour mass; less common to do this before surgery as most detected before becoming too big to be operable (before had to shrink down before surgery)
3 levels of endocrine therapy
ovarian suppression in premenopausal women, blocking oestrogen production by enzymatic inhibition, inhibiting oestrogen responses (anti-oestrogen)
hypothalamo-pituitary-ovarian axis (only premenopausal)
hypothalamus -(peptide GnRH)-> pituitary -(peptides FH and LSH)-> ovary -> large quantities of oestrogens and progesterone to target cells e.g. mammary glands
hypothalamo-pituitary-adrenal axis (pre/post menopausal)
hypothalamus -(CRH)-> pituitary -(ACTH)-> adrenal gland -> androgens, which are converted to oestrogens peripherally (aromatisation), including in ovary, but especially fatty tissue e.g. mammary glands; corticosteroids and progesterone released
hypothalamo-pituitary-prolactin/growth hormone axis
hypothalamus -(dopamine inhibition, TSH and GHRH)-> pituitary -> prolactin and growth hormone
what is the major source of oestrogen biosynthesis in pre-menopausal women
ovary
2 methods of ovarian ablation
surgical oophorectomy, ovarian irradiation (focused radiation)
2 problems of surgical or irradiation ovarian ablation
morbidity, irreversibility (can’t have children)
how can GnRH agonists achieve reversible and reliable medical ovarian ablation (can stop to allow pregnancy, then resume treatment after)
GnRH agonists bind to GnRH receptors in pituitary -> cell surface receptor down-regulation due to overstimulation -> suppression of LH release -> inhibition of ovarian function, including oestrogen production
most common GnRH agonists
goserelin
what inhibitors target ovarian production of oestrogens and progesterones, both from ovary and peripheral conversion of androgens from adrenal glands
aromatase inhibitors
what other treatment can prevent oestrogen action
anti-oestrogens
structure of oestrogens and anti-oestrogens
anti-oestrogens have similar structure to oestrogen, so bind to oestrogen receptor, which can’t then bind to DNA
major anti-oestrogenic therapy which is endocrine treatment of choice for metastatic disease in postmenopausal patients
tamoxifen (efficacy and low incidence of side effects)
how does tamoxifen work
competitive inhibitor of oestadiol binding to ER, negating stimulatory effect of oestrogen and causing cell to be held at G1
most common side effect of tamoxifen
hot flushes
how is tamoxifen given
as prohormone (tamoxifen citrate), which is metabolised in GI tract and liver
what class of drugs does tamoxifen belong to
selective oestrogen receptor modulators (SERMs)
advantageous oestrogenic effects of tamoxifen on bone
prevents osteoporosis by maintaining bone density, as antagonist in breast but agonist in bone
advantageous oestrogenic effects of tamoxifen on CVS
prevents atherosclerosis and lowers low-density cholesterol, as antagonist in breast but agonist in CVS
3 consequences of tamoxifen in uterus
agonist in endometrium, so causes endometrial thickening, hyperplasia and fibroids
3 other consequences of tamoxifen in liver, cataracts and vasculature
increased thromboembolism in liver, increased cataracts, increased vasomotor symptoms
3 additional drugs used in treatment of all stages of breast cancer
toremifene (very similar to tamoxifen), faslodex, raloxifene
consequence of faslodex
oestrogen with huge side chain, purely blocking oestrogen effects causing osteoporosis and CVD
advantage and disadvantage of raloxifene
antagonist of tumour growth and treats osteoporosis, but less effective in breast cancer
what else does tamoxifen reduce the incidence of by 1/3, indicating possible use as prophylactic therapy (prevention)
incidence of contralateral breast cancer (new breast cancer in other breast), indicating use as prophylaxis (prevention)
4 problems associated with using tamoxifen in prevention, hence use of other SERMs or aromatase inhibitors as preventives
increased incidence of endometrial cancer, stroke, DVT, cataracts
major source of oestrogen in postmenopausal women, and where conversion occurs
conversion of adrenal hormones (e.g. androstenedione) to oestrogen, occuring at extra-adrenal or peripheral sites e.g. fat (mammary glands), liver and muscle
what enzyme complex catalyses conversion of adrenal hormones to oestroen
aromatase enzyme complex
what does the aromatase enzyme complex consist of
complex containing cytochrome P450 haem-containing protein and flavoprotein NADPH cytochrome P450 reductase
how many steroid hydroxylations are involved in conversion of androstenedione to oestroen, and what is the prodiuct of the first hydroxylation and significance
3, with estrone sulphate produced in first hyroxylation which is circulated in plasma and taken up by cells and sulphate removed
2 types of aromatase inhibitors which inhibit production of oestrogen
type 1 (irreversible mechanism-based suicide by binding to active site covalently), type 2 (reversible at active site so competetive)
example of type 1 and type 2 aromatase inhibitors
type 1 is exemestane, type 2 is arimidex
response rates to ER+ and PR+ breast cancer and significance
highest, indicating targeting PR is also useful (give progestin to over stimulate pathway and cause down-regulation of receptors)
what is the dominant naturally occuring progestin, and property of progestins that allow use in endocrine treatment of breast and uterine cancers
progesterone, and they are antineoplastic
when is progestin therapy used to treat breast cancer
following selective oestrogen therapy
what is the principal progestin used for treating metastatic breast cancer
megestrol acetate
describe prevalence of resistance to anti-oestrogens used to treat breast cancer
significant proportion of patients presenting with breast cancer, and all patients with metastatic disease, become resistant to each individual endocrine therapy (eventual relapse), even though most cases continue to demonstrate oestrogen responses and contain ER (due to mutation of ER)
how to overcome problem of resistance to tamoxifen and other anti-oestrogens
continue using as they are successful, but require additional therapeutic agents/strategies for endocrine resistant, metastatic disease (e.g. inhibitors of CDKs)
5 other risk factors of breast cancer besides those related to oestrogen exposure
obesity (fat converts androgen to oestrogen), diet, physical inactivity, height, medication (e.g. aspirin)
describe criteria for screening for breast cancer (mammography)
all women between 50-64 once every 3 years; after cancer annual surveillance for at least 5 years to ensure disease free, so know if breast cancer has recurred or is new
2 types of ER positive (80% of breast cancers) breast cancer, and treatment
luminal B/C and luminal A; treated with hormone therapy
3 types of ER negative breast cancer, and treatment
basal like, ErbB2 positive, normal-like; treated with chemotherapy
4 types of basal like ER negative breast cancer
metaplastic, medullary, mucinous, others
treatment for ErbB2 positive ER negative breast cancer
herceptin
biggest detection of breast cancer
self-detection
